The so-called bath salts designer drugs of abuse are powerful and extremely dangerous stimulants that represent an ever-increasing and evolving threat to public health worldwide. Many such preparations have been seized by the authorities and most often contain synthetic derivatives of cathinone. MDPV, mephedrone, and methylone are among the most commonly identified bath salts in recent US seizures. Some of these drugs produce very bizarre, unpredictable, and irrational human behavioral effects. There are major problems in preventing the abuse of these drugs. First, these compounds are relatively simple and cheap to produce from chemicals readily available worldwide. Second, once the U.S. Drug Enforcement Administration (DEA) uses its emergency scheduling authority to place one generation of cathinones (MDPV, mephedrone, and methylone) under Schedule I (the most stringent) regulations, the next generation of structurally and pharmacologically-similar cathinone derivatives (e.g., MDPBP, MDPPP, alpha-PVP, and alpha-PPP) quickly emerge on the market as unregulated replacements. In addition, a large proportion of these substances are produced by Asian criminal groups that complicate interdiction efforts of the DEA and other law enforcement groups. This is not only a U.S. problem as nearly identical situations exist in Europe and elsewhere. In order to gain further insight into the cathinones as a drug class, we synthesized and studied the pharmacologic properties and abuse potential of an array of cathinones including first- (MDPV) and select second-generation (MDPBP, MDPPP, alpha-PVP, and alpha-PPP) synthetic cathinones, and aimed to identify any structural determinants of their actions at monoamine transporters as well as their reinforcing potency and/or effectiveness. Rats were trained to self-administer and rapidly acquired responding for each of the synthetic cathinones by the end of a 10-day acquisition period. When evaluated under an FR5 schedule of reinforcement the rank order for reinforcing potency (i.e., peak dose) was MDPV > alpha-PVP > MDPBP > alpha-PPP > MDPPP = cocaine; these effects were highly correlated with their potency to inhibit uptake at DAT and NET, but not SERT. When evaluated under a PR schedule of reinforcement the rank order for reinforcing effectiveness (i.e., maximum infusions earned) was alpha-PVP = MDPV > alpha-PPP > MDPBP = MDPPP > cocaine; these effects were highly correlated with their selectivity for uptake inhibition at DAT relative to SERT. Our studies indicate that MDPV, alpha-PVP, and their structural analogues all function as highly effective reinforcers, with each of the cathinones maintaining higher levels of responding under a PR than cocaine. The relative reinforcing potency of these MDPV-like cathinones was highly correlated with their potency to inhibit uptake at DAT, and inversely related to the length of the -alkyl side chain (e.g., MDPV > MDPPP). The relative reinforcing effectiveness of these cathinones was highly correlated with their selectivity for DAT over SERT, which is reduced by the presence of the methylenedioxy moiety (e.g., alpha-PVP > MDPV), and related to the length of the alpha-alkyl side chain (e.g., MDPV > MDPPP). Together our studies provide insight into the structure activity relationships of MDPV-like cathinones, and suggest that similar to MDPV and alpha-PVP, the second-generation cathinones are likely to have high potential for abuse.